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Morrissey was born in Liverpool to a family of four. He decided to become an actor after seeing the Ken Loach film Kes and appearing in a school production of The Wonderful Wizard of Oz. While a teenager, Morrissey trained at Liverpool's Everyman Youth Theatre, with Paul McGann's brothers Mark and Stephen. At the age of eighteen, he appeared in the Yorkshire Television/Channel 4 drama One Summer before moving to London to train at the Royal Academy of Dramatic Art.

After graduating from RADA, Morrissey worked on stage for four years with the Royal Shakespeare Company and the National Theatre. In the early 1990s, Morrissey was typecast as policeman and soldiers; he appeared in Black and Blue, Framed (with Timothy Dalton), Between the Lines, Out of the Blue, The One That Got Away (with Paul McGann) and The Knock. Towards the end of the decade, Morrissey played several critically acclaimed roles, including a crooked tax inspector in Holding On, Bradley Headstone in the miniseries adaptation of Charles Dickens' Our Mutual Friend, and pianist Kiffer Finzi in Hillary and Jackie.

In the 2000s, he starred in the films Some Voices and Captain Corelli's Mandolin and the acclaimed miniseries State of Play (with John Simm and Marc Warren). He also played Gordon Brown in the acclaimed TV movie The Deal. In 2004, he starred with David Tennant and Sarah Parish in the musical thriller miniseries Blackpool as crooked gaming kingpin Ripley Holden. He reprised the role for the one-off Viva Blackpool! in 2006, though Tennant and Parish were not involved. The next few years saw Morrissey play the leading male roles in the film flops Basic Instinct 2 and The Reaping. He also appeared in the films Derailed, Stoned and The Water Horse: The Legend of the Deep, and the TV miniseries Cape Wrath and Sense & Sensibility.

In 2008, Morrissey was cast as Jackson Lake in Doctor Who's 2008 Christmas special The Next Doctor. Paparazzi photographs of the episode's location filming in April 2008 coupled with the cliffhanger ending to The Stolen Earth led to tabloid speculation that Morrissey had been cast as the Eleventh Doctor. The rumours intensified when David Tennant announced in October 2008 that he would be leaving the series. Russell T Davies was aware of the speculation, but asked Morrissey not to clarify the episode's plot so attention would be diverted away from the casting of Matt Smith as the real Eleventh Doctor. This caused problems in Morrissey's personal life. He had to reassure his children that the family would not be moving to Wales, where Doctor Who is produced, without revealing anything about the character that they might pass on to schoolfriends.

Despite the speculation, Morrissey's character Jackson Lake had only been led to believe he was the Doctor after Cybermeninfostamps implanted memories of the Doctor's past incarnations inside his head. As he was playing a character with certain Doctor mannerisms, Morrissey allowed himself to be influenced by the performances of William Hartnell, Patrick Troughton and Tom Baker.

In 2009 and 2010, Morrissey appeared in the crime drama miniseries Red Riding (with Andrew Garfield), the John Lennon biopic Nowhere Boy, the crime drama Five Days 2 (with Anne Reid and Penelope Wilton) and the Roman-set film Centurion (with Noel Clarke).

In 2012 and 2013, he played Philip Blake, also know as "the Governor", the main antagonist of season 3 and 4 of in the American series The Walking Dead.